MX2014013599A - Treating hypothalamic obesity with metap2 inhibitors. - Google Patents

Abstract

The invention generally relates to methods of treating a patient suffering from hypothalamic obesity using effective of amounts of a MetAP-2 inhibitor.

Description

TREATMENT OF HYPOTHALAMIC OBESITY WITH INHIBITORS FROM METAP2 CROSS REFERENCE TO RELATED REQUESTS The present application claims priority to US Provisional Application Serial No. 61 / 644,051 filed May 8, 2012, which is hereby incorporated in its entirety by this reference.

BACKGROUND Hypothalamic obesity occurs later or in relation to a pathological process that damages the hypothalamus. This syndrome is characterized by a rapid and constant weight gain that may be accompanied by severe hyperphagia. The weight gain of hypothalamic obesity is different from normal obesity, since it occurs even with caloric restriction. For example, after a hypothalamic lesion, patients develop a voracious hyperphagia that is difficult to contain. In addition, hypothalamic obesity typically does not respond to diet and exercise.

Hypothalamic obesity can occur with any defect or damage of the centers that control the energy of the hypothalamus. In particular, hypothalamic obesity is an unfortunate complication in some brain tumor survivors, especially those who were diagnosed in childhood. It has been estimated that up to 75% of all craniopharyngioma survivors develop severe obesity after diagnosis and treatment, with a rapid increase in body weight after surgical resection of the tumor.

Hypothalamic obesity can also occur with genetic syndromes, such as in patients who have mutations in leptin or the leptin receptor, CART (***e and amphetamine-related transcription), POMC (proopiomelanocortin), prohormone convertase, MC4R (melanocortin receptor 4), singleminded 1 (an essential transcription factor for the formation of supraoptic nuclei and PVN in the hypothalamus) and TrkB. Prader-Willi syndrome, caused by the elimination of genes imprinted by the paternal pathway on chromosome 15q11-ql3 and BBS (Bradet-Biedl syndrome) can also cause hypothalamic obesity. In addition, many psychotropic drugs, for example, clozapine and olanzapine lead to hypothalamic-type obesity.

The hypothalamus regulates body weight by the precise balance of food intake, energy expenditure and amount of body fat tissue. The main hypothalamic areas involved in the regulation of energy (which when damaged cause hypothalamic obesity) include the ventromedial hypothalamus, paraventricular nuclei, arcuate nucleus and the lateral hypothalamic area. In addition, signals from the mass of fatty tissue in the body (including leptin) and the gastrointestinal tract (including g GLP-1, PYY, and / or amylin / pancreatic insulin) affect the centers hypothalamic Disorders involving any interaction of signals of this type with the hypothalamus or damage the hypothalamus, can lead to morbid hypothalamic obesity. Weight gain occurs from the interruption of normal homeostatic functioning of the 10 hypothalamic centers, with loss of control of satiety and hunger, inability to regulate energy balance, reduction of energy expenditure and / or hyperinsulinemia and frequent evolution in diabetes . In contrast, "simple" obesity seems to result from the patient's variability in environmental signals, psychological / emotional state and / or weight-regulating mechanisms.

Despite understanding some of the mechanism of hypothalamic obesity, the treatment of hypothalamic obesity remains unsatisfactory and largely inadequate, in part because there is a lack of well-established preventive or therapeutic strategies. In addition, hypothalamic obesity confers morbidity and significant mortality with a serious negative impact on those, for example, family members who care about these patients.

BRIEF DESCRIPTION OF THE INVENTION The present disclosure generally relates to methods for treating hypothalamic obesity in an obese or overweight patient that includes administering an effective amount of a MetAP-2 inhibitor to a patient in need thereof. A method is also provided herein to optimize weight loss in a patient suffering from hypothalamic injury, which comprises administering a quantity of a MetAP-2 inhibitor to said patient.

For example, herein a method is provided for substantially maintaining body weight or reducing the amount of weight gain in a patient recovering from, or in which, the surgical resection of the craniopharyngioma or radiological treatment of the craniopharyngioma is initiated, which comprises administering an effective amount of a MetAP-2 inhibitor.

Herein also provided is a method of treating, preventing or alleviating hypothalamic obesity in a patient under treatment of schizophrenia or depression comprising administering an effective amount of a MetAP-2 inhibitor. These patients in treatment of schizophrenia or depression were administered or were administered amitriptyline, doxepin, imipramine.clomipramine, maprotin, nortriptyline, trimipramine, paroxetine, mirtazapine, deopramine, isocarboxazid, lithium, valproate, carbamazapine, clozapine, olanzapine, zotepine, quetiapine. , chlorpromazine, thioridazine, perphenazine, trifluoperazine, risperidone, clopentioxol or sulpiride.

The MetAP-2 inhibitors contemplated for use in the disclosed methods include substantially irreversible inhibitors, for example, a MetAP-2 inhibitor is selected from the group consisting of a fumagillin, fumagillol or fumagillin ketone, siRNA, shRNA, an antibody or a compound antisense, or 0- (4-dimethylaminoethoxycinnamoyl) fumagillol and salts pharmaceutically acceptable of these. Reversible inhibitors are also contemplated.

Human patients can have an initial body mass index of at least about 30 kg / m2, at least about 35 kg / m2, or at least 40 kg / m2. Adolescent patients or children may have a body mass index above 95 percentile for children of the same age and sex, or a lower body mass index but a clear cause for hypothalamic obesity that would benefit from the previous intervention. Also contemplated herein is a method for substantively preventing hypothalamic obesity in a patient suffering from hypothalamic injury, including administering a MetAP-2 inhibitor (eg, a described MetAP-2 inhibitor), wherein the patient has an index of body mass that does not correspond to obesity (for example, in the normal range or overweight), but is at risk of developing hypothalamic obesity.

The contemplated administration includes oral, subcutaneous and / or intravenous administration.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates the change in body weight (percentage) of C57 / BL6 mice treated with a single dose of 0.5 g / kg gold thioglucose, and after 40 days, a subcutaneous dose of 0.1 mg / kg was started daily of 6-O- (4-dimethylaminoethoxy) cinnamoyl fumagillol (ZGN-440).

Figure 2 illustrates the normalized food intake in GTG mice at the level of normal mice that were not treated with gold thioglucose, after the subcutaneous dose of 0.1 mg / kg daily of 6-0- (4-dimethylaminoethoxy) cinnamoyl fumagillol.

Figure 3 illustrates the reduction in percentage of body weight in up to seven weeks of treatment with 6-0- (4-dimethylaminoethoxy) cinnamoyl fumagillol (ZGN-440; average dose of 1.44 mg administered twice a week by subcutaneous administration, n = 5) or placebo (administered twice a week by subcutaneous administration, n = 2) in obese human patients treated otherwise for depression with mirtazapine, sertraline, imipramine, paroxetine or amitriptyline.

DETAILED DESCRIPTION OF THE INVENTION Methods A method for treating hypothalamic obesity in a patient in need thereof and / or a method for reducing body weight in a patient suffering from hypothalamic injury is provided herein, which comprises administering to the patient, daily or less frequently than daily , a dose of a formulation comprising a therapeutically effective amount of a 6-0- (4-dimethylaminoethoxy) cinnamoyl fumagillol compound or pharmaceutically acceptable salts thereof. These methods it may include administering to the patient a single dose of the formulation about every other day (for example, every two days), twice a week, (for example, every 3 days, every 4 days, every 5 days, every 6 days or, for example, administered with an interval of around 2 to about 3 days between doses), once a week, week by week, twice a month, once a month or even less frequently. It will be understood that methods that include administering a single dose less infrequently may, in some embodiments, be a method directed at maintaining a specific weight, such as a more optimal body weight after treatment using other methods described herein. . The described methods may include, for example, administering a dose of a described compound at a frequency less than daily until a desired weight is achieved.

In some embodiments, the methods described relate to treating hypothalamic obesity that is the result of hypothalamic injury due to infiltrating disease, tumor (e.g., such as an epithelioma, angiosarcoma, cholesteatoma, pinealoma, greminoma, endothelioma, hamartoma, chordoma, colloid cysts, epidermoid, ganglioneuroma, ependymoma, glioma, meningioma, pituitary macroadenoma, teratoma, leukemia, Langerhans cell or metastatic tumor), neurosurgery, radiation or head trauma. For example, a method for treating, improving and / or substantively preventing hypothalamic obesity that is a result of craniopharyngioma or after a Radiological treatment of craniopharyngioma in a patient.

In the present methods are contemplated to treat patients who have hypothalamic obesity due to, (or treat patients who are at risk of having hypothalamic obesity due to) a disease such as sarcoidosis, tuberculosis, araenoiditis, histiocytosis X or encephalitis. In other modalities, methods are contemplated to treat patients with hypothalamic obesity, where hypothalamic obesity is a result of cranial radiotherapy or cerebral aneurysm, due to Prader-Willi syndrome or Bardet-Biedi syndrome, or due to a simple genetic mutation. or multiple.

For example, a method for maintaining substantial body weight or reducing the amount of weight gain in a patient recovering from, or in which, craniopharyngioma surgery or radiological treatment of the craniopharyngioma, which it comprises administering an effective amount of a MetAP-2 inhibitor. The present invention also provides a method for substantially maintaining body weight, or minimizing weight gain in a patient suffering from Prader-Willi syndrome or Bardet-Biedi syndrome, which comprises administering an effective amount of a MetAP-2 inhibitor.

Herein is provided a method for treating hypothalamic obesity in a patient in treatment of schizophrenia or depression, and / or other associated mental disorders, and where the patient is administered or administered a medication that has as a side effect an obesity hypothalamic type (for example, amitriptyline, doxepin, imipramine, clomipramine, maprotiine, nortriptyline, trimipramine, paroxetine, mirtazapine, deopramine, isocarboxazid, lithium, valproate, carbamazapine, clozapine, olanzapine, zotepine, quetiapine, chlorpromazine, thioridazine, perphenazine, trifluoperazine, risperidone, clopentioxol or sulpiride), which comprises administering an amount effective inhibitor of MetAP-2 described.

The patients contemplated can be a human being, (for example, an adult or a child under 18 years of age), or a companion animal such as a cat or a dog.

A method for treating hypothalamic obesity in a patient in need, and / or a method for reducing body weight, or minimizing or substantially preventing significant weight gain in a patient suffering from hypothalamic injury, is provided herein, which comprises administering to the patient a dose of a formulation comprising a therapeutically effective amount of a compound 6-O- (4-dimethylaminoethoxy) cinnamoyl fumagillol or pharmaceutically acceptable salts thereof, for a first period of time, is retained for a second period of time, and again optionally administered for a third period of time, for example, alternative dosing regimens. For example, during the first period of time a formulation can be administered to a patient described daily, every other day, every three, four or five days, biweekly, monthly or annually; during the second period of time (for example, 1 day, 1 week, 2 weeks, 1 month) no dose is administered; and during, for example, a third period of time, it can be administered to the patient in a regime similar or different to the first period of time, for example, every other day, every three, four or five days, biweekly, monthly or annually. In each administration or period of time, the route of administration may be different or equal to another period of time.

The therapeutically effective amount administered in the described methods such as those described above can provide the patient with a body weight loss of about 0.3% to about 2%, about 0.4% to about 2%, or about 0.5% at about 2% or more, or about 0.5 kg to about 2 kg or more of the patient's initial weight even after the initial dose, or after the administration of two doses, or after administration after a first period of time, for example, such methods can cause weight loss for three or four days or more after administration (eg, parenteral (eg, intravenous) administration) of a single dose. For example, a patient, after receiving a first dose and / or after receiving a subsequent dose, can continue with the weight loss for three or four days or more without further administration of a described compound. In some embodiments, administration of a first initial dose or administration of a first and second dose (e.g., both administered in the same week), may provide about 0.5 kg to about 2 kg or more of weight loss. Subsequent administration may cause weight loss additional until a target weight of the patient is achieved.

In one embodiment, a method for improving or preventing substantial weight gain in a patient suffering from a new hypothalamic lesion, for example, by administering a MetAP2 inhibitor immediately or substantially immediately described following said injury, for example , within 1 day, 1 week, 2 weeks, or within 3 weeks, or within a month or more after the injury.

In another embodiment, effective dosages are provided herein, for example, a daily dosage of a MetAP2 inhibitor, which substantially can not modulate or suppress angiogenesis. For example, methods are provided herein that include administering doses of MetAP2 inhibitors that are effective for weight loss, but are doses significantly smaller than that required to modulate and / or suppress angiogenesis (which may typically require 12.5 mg / kg to around 50 mg / kg or more). For example, the contemplated dosage of a MetAP2 inhibitor in the methods described herein may include administering about 25 mg / day, about 10 mg / day, about 5 mg / day, about 3 mg / day, around of 2 mg / day, about 1 mg / day, about 0.75 mg / day, about 0.5 mg / day, about 0.1 mg / day, about 0.05 mg / day or about 0.01 mg / day.

For example, an effective amount of the drug for weight loss in a patient may be from about 0.0001 mg / kg to about 25 mg / kg of body weight per day. For example, a contemplated dosage may be from about 0.001 to 10 mg / kg of body weight (eg, per day or per day), about 0.001 mg / kg to 1 mg / kg of body weight, about 0.001 mg / kg at 0.1 mg / kg of body weight or about 0.005 to about 0.04 mg / kg or about 0.005 to about 0.049 mg / kg of body weight, about 0.01 to about 0.03 mg / kg of body weight , or around 0.005 to about 0.02 mg / kg. In one embodiment, a MetAP2 inhibitor such as that described herein (e.g., 0- (4-dimethylaminoethoxycinmoyl) fumagillol), about 0.005 to about 0.04 mg / kg of a patient or other dosage amount may be administered. as described herein.

The doses contemplated, administered with a frequency lower than daily, can be a fixed dose, for example, around 0.3 mg, 0.5 mg, 1 mg, 2 mg, 1.5 mg, 1.8 mg, 2.5 mg, 3.0 mg, 4 mg, 5 mg or even 6 mg, for example, about 0.5 mg to about 3.0 mg or about 0.1 mg to about 2 mg. In other embodiments, a therapeutically effective amount is based on excess body weight (or excess adipose tissue), eg, at least about 30 mg of a compound described per kg of excess adipose tissue, (or excess weight) body) of the patient, or at least about 40 pg per kg or more of excess adipose tissue, (or excess body weight) of the patient, for example, about 30 pg per kg of excess adipose tissue (or excess of adipose tissue). body weight) to around 60 pg per kg, around 40 pg per kg to around 60pg per kg, or about 35 mg per kg to about 45pg per kg, or about 35 pg per kg to about 50 pg per kg of excess adipose tissue (or excess body weight).

For example, a method for treating obesity in a patient in need thereof, which comprises administering it, parenterally (for example, intravenously) or non-parenterally (orally), about 0.005 to about 0.04 mg is provided herein. / kg or about 0.01 to about 0.03 mg / kg, or about 0.01 to about 0.1 mg / kg of a MetAP2 inhibitor that is selected from 0- (4-dimethylaminoethoxycinnamoyl) fumagillol and pharmaceutically acceptable salts thereof (by example, an oxalate salt), to said patient. Said method, after administration of said MetAP2 inhibitor, for example, daily or weekly, for about 3, 4, 5 or 6 months or more may result in at least 10%, 20%, 30% or 40% or more Weight loss based on the patient's original weight.

Therapeutically effective doses can be calculated, for example, as a function of body surface area (BSA), which can be determined using formulas such as those described by Mosteller (Mosteller RD, NEngl JMed 1987 Oct 22; 317 (17): 1098), where the BSA is calculated in SI units (international system of units) as BSA (m2) = ([height (cm) x weight (kg)] / 3600) 1/2 (for example, BSA = SQRT ((cm * kg) / 3600)), or US units (United States system of measures), where the BSA (m2) = ([height (in) x weight (lb)] / 3131Jl / 2. In some embodiments, the therapeutically effective amount administered (e.g., intravenously) to the patient using a method described is from about 0.5 mg / m2 to about 1.5 mg / m2, or about 0.9 mg / m2 (or about 10 to 20 mg per kilo of total body weight) or more than one compound described. In other embodiments, a therapeutically effective amount is based on excess body weight (or excess adipose tissue), eg, at least about 30 pg of a compound described per kg of excess adipose tissue, (or excess weight) body) of the patient, or at least about 40 pg per kg or more of excess adipose tissue, (or excess body weight) of the patient, for example, about 30 pg per kg of excess adipose tissue (or excess of adipose tissue). body weight) at about 60 pg per kg, about 40 pg per kg to about 60 pg per kg, or about 35 pg per kg to about 45pg per kg, or about 35 pg per kg to about 50 pg per kg of excess adipose tissue (or excess body weight).

In another embodiment, there is provided a method for treating obesity in a patient in need, which comprises administering an effective amount of a MetAP-2 inhibitor, wherein the effective amount is proportional to the excess body weight of said patient. For example, in some embodiments, said effective amount may not be proportional to the total body weight. A method for treating obesity in a patient in need thereof is also provided, which comprises determining the excess body weight or excess adipose tissue of said patient; determine a dose effective of a MetAP-2 depending on the excess body weight or excess adipose tissue of said patient; and administering the effective dose to said patient.

For example, the described methods may include administering (e.g., parenterally) administering to the patient a single dose of at least about 40 mg of eO - ^ - dimethylaminoethoxycinmoyl fumagillol or pharmaceutically acceptable salts thereof, per kg of excess tissue adipose of the patient, for example, daily, with a frequency lower than daily, etc. In some embodiments, such methods may additionally include a second dose of at least about 40 pg of 6-O- (4-dimethylaminoethoxycinmoyl fumagillol or pharmaceutically acceptable salts thereof, per kg of excess body weight of the patient at least about 4. days after administration of the single dose For example, a second dose may be administered at intervals, for example, three or four days or more In other embodiments, the described methods may additionally include administering subsequent doses of an inhibitor of MetAP2 (for example, -O-^ - dimethylaminoethoxycinmoyl fumagillol) at intervals of between about 4 days and 1 month.

Also provided herein is a method for optimizing weight loss in a patient undergoing weight loss treatment and suffering from hypothalamic injury is provided, comprising a) administering an amount of a MetAP-2 inhibitor to said patient; b) determine the increase of adiponectin in said patient; and c) increasing the amount of the MetAP-2 inhibitor administered to the patient if the change in adiponectin in the patient is less than an increase of about 60% or more (or 50% or more, eg, 30% to about 60% compared to the patient's adiponectin level before administration of the MetAP-2 inhibitor.

In another embodiment, a method is provided for optimizing weight loss in a patient undergoing weight loss treatment and suffering from hypothalamic injury is provided, comprising a) administering an amount of a MetAP-2 inhibitor to said patient; b) determine the increase of adiponectin in said patient; c) increasing the amount of the MetAP-2 inhibitor administered to the patient if a reduction in the ratio of leptin to adiponectin in the patient's plasma is not greater than 50%, or no greater than 40%, for example, reduction The ratio of leptin to adiponectin is reduced by about 10%, 20%, 30% or 40%.

In one embodiment, a method for treating or ameliorating hypothalamic obesity in a patient in need thereof, comprising administering a MetAP-2 inhibitor described to a patient in conjunction with bariatric surgery, eg, before and / or after said surgery .

In addition to having overweight or hypothalamic obesity, a patient may be suffering from co-morbidities related to overweight or obesity, that is, diseases and other adverse health conditions associated with, exacerbated by or precipitated by being overweight or obesity. Since overweight or obesity is associated with other adverse health conditions or co-morbidities, for example, diabetes, the administration of MetAP2 inhibitors may be beneficial to improve, stop the development of or, in some cases, even eliminate, these conditions or co-morbidities related to overweight or obesity. In some embodiments, the described methods include co-administration with hormones such as growth hormones that may be necessary in patients with hypothalamic injury. In some embodiments, the methods provided herein may additionally include administering at least one other agent in addition to a MetAP2 inhibitor, for example, an agent directed to the treatment of these conditions related to overweight or obesity.

Other agents contemplated include those administered to treat type 2 diabetes such as sulfonylureas (e.g., chloropropamide, glipizide, glyburide, glimepiride); meglitinides (e.g., repaglinide and nateglinide); biguanides (for example, metformin); thiazolidinediones (rosiglitazone, troglitazone and pioglitazone); glucagon-1 mimetic peptides (e.g., exenatide and liraglutide); sodium-glucose cotransporter inhibitors (e.g., dapagliflozin), renin inhibitors and alpha-glucosidase inhibitors (e.g., acarbose and meglitol), and / or those administered to treat cardiac disorders and conditions such as hypertension, dyslipidemia, disease ischemic heart disease, cardiomyopathy, cardiac infarction, stroke, thromboembolic disease venous and pulmonary hypertension, which are related to overweight or obesity, for example, chlorthalidone; hydrochlorothiazide; indapamide, metolazone, loop diuretics (eg, bumetanide, ethacrynic acid, furosemide, lasix, torsemide); potassium sparing agents (e.g., amiloride hydrochloride, spironolactone and triamterene); peripheral agents (eg, reserpine); alpha-central agonists (eg, clonidine chlorohydrate, guanabenz acetate, guanfacine hydrochloride and methyldopa); alpha blockers (eg, doxazosin mesylate, prazosin hydrochloride and terazosin hydrochloride); beta blockers (eg, acebutolol, atenolol, betaxolol, nisoprolol fumarate, carteolol hydrochloride, metoprolol tartrate, metoprolol succinate, Nadolol, penbutolol sulfate, pindolol, propranolol hydrochloride and timolol maleate); alpha and beta blockers combined (eg, carvedilol and labetalol hydrochloride); direct vasodilators (eg, hydralazine hydrochloride and minoxiedil); calcium antagonists (e.g., diltiazem hydrochloride and verapamil hydrochloride); dihydropyridines (e.g., amlodipine besylate, felodipine, isradipine, nicardipine, nifedipine and nisoldipine); ACE inhibitors (benazepril hydrochloride, captopril, enalapril maleate, fosinopril sodium, lisinopril, moexipril, quinapril hydrochloride, ramipril, trandolapril); angiotensin II receptor blockers (eg losartan potassium, valsartan and Irbesartan); and combinations thereof, as well as statins such as mevastatin, lovastatin, pravastatin, simvastatin, velostatin, dihydrocompactin, fluvastatin, atorvastatin, dalvastatin, carvastatin, crilvastatin, bevastatin, cefvastatin, rosuvastatin, pitavastatin and glenvastatin, typically for the treatment of dyslipidemia.

Other agents that can be co-administered (eg, sequentially or simultaneously) include agents administered to treat ischemic heart diseases including statins, nitrates (e.g., isosorbide dinitrate and isosorbide mononitrate), beta-blockers, and calcium channel blockers , agents administered to treat cardiomyopathy including inotropic agents (eg, digoxin), diuretics (e.g., furosemide), ACE inhibitors, calcium antagonists, antiarrhythmic agents (e.g., sotolol, amiodarone and disopyramide) and beta-blockers, agents administered for treat cardiac infarction including ACE inhibitors, angiotensin II receptor blockers, direct vasodilators, beta-blockers, antiarrhythmic agents and thrombolytic agents (eg, alteplase, retaplasa, tenecteplase, anistreplase and urokinase), agents administered to treat strokes including antiplatelet agents (for example eg, aspirin, clopidogrel, dipyridamole and ticlopidine), anticoagulant agents (e.g., heparin) and thrombolytic agents, agents administered to treat venous thromboembolic diseases including antiplatelet agents, anticoagulants and thrombolytic agents, agents administered to treat pulmonary hypertension including agents inotropic agents, anticoagulants, diuretics, potassium (for example, K-dur), vasodilators (eg example, nifedipine and diltiazem), bosentan, epoprostenol and sildenafil, agents administered to treat asthma including bronchodilators, anti-inflammatory agents, leukotriene blockers and anti-Ige agents. Particular agents for asthma include zafirlukast, flunilsolide, triamcinolone, beclomethasone.terbutaline, fluticasone, formoterol, beclomethasone, salmeterol, theophylline and xopenex, agents administered to treat sleep apnea include modafinil and amphetamines, agents administered to treat liver disease nonalcoholic fat include antioxidants (eg, vitamins E and C), insulin sensitizers (metformin, piogli tazone, rosiglitazone and betaine), hepatoprotectors and lipid-lowering agents, agents administered to treat osteoarthritis of joints that support weight include acetaminophen, non-steroidal anti-inflammatory agents (eg, ibuprofen, etodolac, oxaprozin, naproxen, diclofenac and nabumetone), COX-2 inhibitors (eg, celecoxib), steroids, supplements (eg, glucosamine and chondroitin sulfate) and artificial synovial fluid , agents administered to treat Prader-Wi syndrome lli include human growth hormone (HGH), somatropin and weight loss agents (eg, orlistat, Sibutramine, methamphetamine, ionamine, phentermine, bupropion, diethylpropion, phendimetrazine, benfeptide and topamax), agents administered for treating polycystic ovarian syndrome include insulin sensitizers, synthetic estrogen and progesterone combinations, spironolactone, eflornithine and clomiphene, agents administered to treating erectile dysfunction include phosphodiesterase inhibitors (eg, tadalafil, sildenafil citrate and vardenafil), prostaglandin E analogs (eg, alprostadil), alkaloids (eg, yohimbine) and testosterone, agents administered to treat infertility include clomiphene, clomiphene citrate, bromocriptine, gonadotropin-releasing hormone (GnRH), GnRH agonist, GnRH antagonist, tamoxifen / nolvadex, gonadotropins, human chorionic gonadotropin (HCG), human menopausal gonadotropin (HmG), progesterone, recombinant follicle stimulating hormone (FSH), urofollitropin, heparin, follitropin alfa and follitropin beta, agents administered to treat obstetric complications include bupivacaine hydrochloride, dinoprostone PGE2, meperidine HCI, ferro-folic -500 / iberol-folic-500, meperidine, methylergonovine maleate, ropivacaine HCI, HCI nalbuphine, oxymorphone HCI, oxytocin, dinoprostone, ritodrine, scopolamine hydrobromide, sufentanil citrate and oxytocin, agents administered to treat depression include serotonin reuptake inhibitors (eg, fluoxetine, escitalopram, citalopram, paroxetine, sertraline and venlafaxine); tricyclic antidepressants (eg, amitriptyline, Amoxapine, clomipramine, desipramine, dosulepine hydrochloride, doxepin, imipramine, iprindol, lofepramine, nortriptyline, opipramol, protiptilin, and trimipramine); monoamine oxidase inhibitors (eg isocarboxazide, moclobemide, phenelzine, tranylcypromine, selegiline, rasagiline, nialamide, iproniazide, iproclozide, toloxatone, linezolid, dienolide kavapirone demethoxyangin and dextroamphetamine); psychostimulants (for example, amphetamines, methamphetamines, methylphenidate and arecoline); antipsychotics (eg, butyrophenones, phenothiazines, thioxanthenes, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, symbyax, tetrabenazine, and cannabidiol); and mood stabilizers (eg, lithium carbonate, valproic acid, divalproex sodium, valproate sodium, lamotrigine, carbamazepine, gabapentin, oxcarbazepine, and topiramate), agents administered to treat anxiety include serotonin reuptake inhibitors, mood stabilizers , benzodiazepines (eg, alprazolam, clonazepam, diazepam and lorazepam), tricyclic antidepressants, monoamine oxidase inhibitors and beta blockers, and other weight loss agents, including serotonin and noradrenergic reuptake inhibitors; inhibitors of noradrenergic reuptake; inhibitors of the selective reuptake of serotonin; and intestinal lipase inhibitors. Particular agents of weight loss agents include orlistat, sibutramine, methamphetamine, ionamine, phentermine, bupropion, diethylpropion, phendimetrazine, benzephemate and topamax.

The modes of administration of Met-AP2 inhibitors contemplated in the disclosed methods include subcutaneous, intravenous or oral administration. For example, injectable preparations are contemplated, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known technique using dispersing or wetting agents and lubricating agents. adequate suspension.

The treatment regimens described or contemplated may include a corrective phase during which a dose of a MetAP2 inhibitor sufficient to provide a reduction in excess adiposity is administered, for example, initially after the hypothalamic lesion (eg, after the surgery) followed by a maintenance phase, during which a lower or equivalent dose of a sufficient MetAP2 inhibitor can be administered to prevent re-development of excess adiposity.

Obesity and overweight refer to an excess of fat in proportion to lean body mass. The accumulation of excess fat is associated with the increase in size (hypertrophy) as well as the amount (hyperplasia) of adipose tissue cells. Obesity is measured in several ways in terms of absolute weight, weight-height ratio, degree of excess body fat, distribution of subcutaneous and / or visceral fat, and social and aesthetic rules. A common measure of body fat is the Body Mass Index (BMI). BMI refers to the ratio of body weight (expressed in kilograms) to height squared (expressed in meters). The body mass index can be calculated accurately using the formulas: SI units: BMI = weight (kg) / (height2 (m2), or US units: BMI = weight (lb) * 703) / (height2 (in2).

According to the Centers for Disease Control and Prevention of the United States (CDC), an overweight adult has a BMI of 25 kg / m2 to 29.9 kg / m2, and an obese adult has a BMI of 30 kg / m2 or more. A BMI of 40 kg / m2 or more is indicative of morbid obesity or extreme obesity. For children, the definitions of overweight and obesity take into account age, height and gender, as they refer to the appropriate amounts of body fat and are not strictly based on BMI calculations. It can be seen that for certain patients (for example, certain ethnic groups, for example, Asian) a lower BMI can be considered as overweight or obesity.

BMI does not represent the fact that excess adipose tissue can occur selectively in different parts of the body and the development of adipose tissue may be more dangerous to health in some parts of the body than in other parts of the body. For example, "central obesity", typically associated with an "apple-shaped" body, is the result of excess adiposity especially in the abdominal region, including abdominal and intra-abdominal fat or visceral fat, and poses a high risk of comorbidity than "peripheral obesity," which is typically associated with a "pear-shaped" body that is the result of excess adiposity especially in the hips. The measurement of the waist / hip circumference index (ICC) can be used as an indicator of central obesity. A minimum ICC indicative of central obesity has been established, variably, and an adult central obesity typically has an ICC of around 0.85 or greater in the case of a woman and around 0.9 or greater in the case of a man . The methods to determine if a subject has Being overweight or obese considering the relationship of excessive adipose tissue with respect to lean body mass may involve obtaining a body composition of the subject. Body composition can be obtained by measuring the thickness of subcutaneous fat in multiple places in the body, such as the abdominal area, the subscapular region, arms, buttocks and thighs. These measurements are then used to calculate total body fat with a margin of error of approximately four percentage points. Another method is the bioelectrical impedance analysis (AIB), which uses the resistance of the electrical flow through the body to calculate body fat. Another method is to use a large water tank to measure the buoyancy of the body. An increase in body fat will result in greater flotation, while greater muscle mass will result in a tendency to sink. Still another method is dual energy x-ray absorptiometry in a fan beam (DEXA). DEXA allows body composition, particularly the total body fat and / or regional fat mass, to be determined non-invasively.

An excess in body weight can be evaluated, for example, by comparing the weight of a patient in need of treatment with the weight that the patient would achieve with a desirable BMI, for example, non-obese (for example, a desirable BMI of around 25 or less). For example, the excess body weight of a patient who measures 1.6 m in height, who weighs 89.6 kg (and who has a BMI of 35) can be found by calculating the weight required for a BMI of 25 (that is, around 64). kg); the initial excess of the body weight of said patient would be around 89.6-64 = 25.6 kg.

MetAP2 inhibitors MetAP2 inhibitors refer to a class of molecules that inhibits or modulates MetAP2 activity, for example, the ability of MetAP2 to cleave the methionine residue at the N-terminus of newly synthesized proteins to produce the active form of the protein or the ability of MetAP2 to regulate protein synthesis by protecting the eukaryotic start factor 2 subunit (elF2) from phosphorylation.

Examples of MetAP2 inhibitors may include irreversible inhibitors that bind, covalently, to MetAP2. For example, said irreversible inhibitors include fumagillin, fumagillol and fumagillin ketone.

The fumagillin derivatives and analogs and pharmaceutically acceptable salts thereof are contemplated herein as irreversible inhibitors of MetAP2, such as 0- (4-dimethylaminoethoxycinnamoyl) fumagillol (also referred to herein as Compound A), 0- (3,4,5-trimethoxycinnamoyl) fumagillol, 0- (4-chlorocinnamoyl) fumagillol; 0- (4- aminocinnamoyljfumagilol; 0- (4-dimethylaminoethoxycinmoyljfumagilol; 0- (4-methoxycinnamoyl) fumagillol; 0- (4-dimethylaminocinamoyljfumagilol; 0- (4-hydroxycinnamoyl) fumagillol; 0- (3,4- dimethoxycinnoyl) fumagillol; 0- (3,4-methylenedioxycinnamoyl) fumagillol; 0- (3,4,5-trimethoxycinnamoyl) fumagillol; 0- (4-nitrocinnamoyl) fumagillol; 0- (3,4-dimethoxy-6-aminocinnamoyljfumagilol; 0- (4-acetoxy-3,5-dimethoxycinnamoyl) fumagillol; 0- (4-ethylaminocinamoyl) fumagillol; 0- (4-ethylaminoethoxycinnamoyl) fumagillol; -dimethylaminomethyl-4-methoxycinnamoyl) fumagillol; 0- (4-trifluoromethylcinnamoyl) fumagillol; 0- (3,4-dimethoxy-6-nitrocinnamoyl) fumagillol; O- (4-acetoxycinnamoyl) fumagillol; 0- (4-cyanocinnamoyl) fumagillol; 4- (4-methoxycinmoyl) oxy-2- (1,2-epoxy-l, 5-dimethyl-4-hexenyl) -3-methoxy-1-chloromethyl-1-cyclohexanol; 0- (3,4,5 - trimethoxycinnamoyl) fumagillol; 0- (4-dimethylaminocinnamoyl) fumagillol; 0- (3,4,5-trimethoxycinnamoyl) oxy-2- (1,2-epoxy-1,5-dimethyl-4-hexenyl) -3-m-ethoxy-1-chloromethyl-1-cyclohexanol; 0- (4-dimethylaminocinamoyl) oxy-2- (1,2-epoxy-1,5-dimethyl-4-hexenyl) -3-methoxy- 1-chloromethyl-1-cyclohexanol; 0- (3,5-dimethoxy-4-hydroxycinnamoyl) fumagillol or O- (chloracetyl-carbamoyl) fumagillol (TNP-470), and / or pharmaceutically acceptable salts thereof (eg, oxalate) of 0- (4-dimethylaminoethoxycinnamoyl) fumagillol).

Furmagilin, and some derivatives thereof, have a carboxylic acid moiety and can be administered in the form of the free acid. Alternatively, pharmaceutically acceptable salts of fumagillin, fumagillol and derivatives thereof are contemplated herein.

The pharmaceutically acceptable salts include, by way of illustration, those which can be made using the following bases: ammonia, L-arginine, benetamine, benzathine, betaine, bismuth, hydroxide trace, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethylenediamine, N-methylalglucarnine, hydrabamine, 1 H-imidazole, lysine, magnesium hydroxide, 4- (2-hydroxyethyl) morpholine, piperazine, hydroxide of potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium hydroxide, triethanolamine, zinc hydroxide, dicyclohexylamine, or any other electron pair donor (such as Handbook of Pharmaceutical Salts, Stan &Wermuth, VHCA and Wilcy, Uchsenfurt-Hohestadt Germany, 2002). The pharmaceutically acceptable salts contemplated may include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, fumaric acid, tartaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid or paratoluenesulfonic.

The esters of the present invention can be prepared by reacting for example, fumagillin or fumagillol with the appropriate acid under standard esterification conditions described in the literature (Houben-Weyl 4a Ed. 1952, Methods of Organic Synthesis). Suitable fumagillin esters include ethyl methanoate, ethyl ethanoate, ethyl propanoate, propyl methanoate, propyl ethanoate and methyl butanoate.

In another embodiment, the contemplated irreversible MetAP2 inhibitors may include a siRNA, shRNA, antibody or an antisense compound of MetAP2.

Additional examples of reversible and irreversible MetAP2 inhibitors are provided in the following references, each of which which is incorporated herein by reference. Olson et al. (US 7,084,108 and WO 2002/042295), Olson et al. (US 6,548,477, US 7,037,890, US 7,084,108, US 7,268,111, and WO 2002/042295), Olson et al. (WO 2005/066197), Hong et al. (US 6,040,337), Hong et al. (US 6,063,812 and WO 1999/059986), Lee et al. (WO 2006/080591), Kishimoto et al. (US 5,166,172; US 5,698,586; US 5,164,410; and 5,180,738), Kishimoto et al. (US 5,180,735), Kishimoto et al. (US 5,288,722), Kishimoto et al. (US 5,204,345), Kishimoto et al. (US 5,422,363), Liu et al. (US 6,207,704; US 6,566,541; and WO 251998/056372), Craig et al. (WO 1999/057097), Craig et al. (US 6,242,494), BaMaung et al .. (US 7,030,262), Comess et al. (WO 2004/033419), Comess et al. (US 2004/0157836), Comess et al. (US 2004/0167128), Henkin et al .. (WO 2002/083065), Craig et al. (US 6,887,863), Craig et al. (US 2002/0002152), Sheppard et al. (2004, Bioorganic &Medicinal Chemistry Letters 14: 865-868), Wang et al. (2003, Cancer Research 63: 7861-7869), Wang et al. (2007), (Bioorganic &Medicinal Chemistry Letters 17: 2817-2822), Kawaiet al. (2006, Bioorganic &Medicinal Chemistry Letters 16: 3574-3577), Henkin et al. (WO 2002/026782), Nan et al. (US 2005/0113420), Luo et al. (2003, J. Med. Chem., 46: 2632-2640), Vedantham et al. (2008, J. Comb. Chem., 10: 195-203), Wang et al. (2008, J. Med. Chem., 51 (19): 6110-20), Ma et al. (2007, BMC Structural Biology, 7:84) and Huang et al. (2007, J. Med. Chem., 50: 5735-5742), Evdokimov et al. (2007, PROTEINS: Structure, Function, and Bioinformatics, 66: 538-546), Garrabrant et al. (2004, Angiogenesis 7: 91-96), Kim et al. (2004, Cancer Research, 64: 2984-2987), Towbin et al. (2003, The Journal of Biological Chemistry, 278 (52): 52964-52971), Marino Jr. (U.S. Patent No. 7,304,082), Kallender et al. (U.S. patent application number 2004/0192914), and Kallender et al. (US patent application numbers 2003/0220371 and 2005/0004116). Other MetAp2 inhibitors contemplated herein are described in U.S.S.N.61 / 310, 776; 61 / 293,318; 61 / 366,650 and PCT / US10 / 52050 (all of the foregoing are hereby incorporated by reference in their entirety).

For example, the contemplated MetAP2 inhibitors may include: .

EXAMPLES The examples that follow are not intended to limit, in any way, the scope of this invention, but are provided to illustrate aspects of the methods described. Other various embodiments of this invention will be apparent to the person skilled in the art.

EXAMPLE 1 Mouse model of hypothalamic lesion Gold thioglucose (GTG) is a chemical treatment used as a hypothalamic lesion model. C57 / BL6 mice were treated with a single dose of 0.5 g / kg of gold thioglucose. After 40 days, a cohort was started with a daily subcutaneous dose of 0.1 mg / kg of 6-O- (4-dimethylaminoethoxy) cinnamoyl fumagillol (ZGN-440).

A significant weight loss was observed in the treated mice, approximate to the weight loss observed in other obesity models. (Figure 1). The food intake level of the GTG-treated mice increased to more than 3 g / day / mouse, where in the GTG mice treated with ZGN-440 the food intake decreased to the level of the normal mice that were not treated with thioglucose. gold (less than 3 g / day) (Figure 2).

EXAMPLE 2 Effects of treatment of humans treated, otherwise, with antidepressants known to cause hypothalamic obesity Significant weight loss was observed over a period of up to seven weeks of treatment of obese humans also taking antidepressant medications (e.g., mirtazapine, sertraline, imipramine, paroxetine and amitriptyline) known to induce an increase in body weight and obesity . Five of these patients were also given ZGN-440 (an average dose of 1.44 mg, administered twice a week by subcutaneous administration). On average, patients lost 5.4 percent of their reference body weight during the seven-week treatment. Conversely, similar patients (who also took antidepressant medications known to induce weight gain and obesity, including mirtazapine, sertraline, imipramine, paroxetine and amitriptyline), treated with a placebo, administered twice a week by subcutaneous administration, They could not lose weight. At the reference point, the average body weight (± SEM) was 100.2 ± 3.2 kg and the average body mass index was 38.8 ± 1.7 kg / m2. Weight loss was statistically significant for ZGN-440 against placebo as indicated (p-values were obtained using the Student's t test to determine the percentage change in body weight from the reference point). (Figure 3).

Incorporation by reference References and quotations were made to other documents, such as patents, patent applications, patent publications, newspapers, books, newspapers, web content, through the present description. All such documents are incorporated herein in their entirety by this reference, for all purposes.

Equivalents Various modifications of the invention and several additional embodiments thereof, in addition to those shown and described herein, will be apparent to those skilled in the art from the contents totals of this document, including references to scientific and patent literature cited herein. The object of the present contains important information, examples and guides that can be adapted to the practice of this invention in its various and equivalent modalities of these.

Claims (54)

NOVELTY OF THE INVENTION CLAIMS

1. The use of a MetAP-2 inhibitor to prepare a medicament for treating and / or minimizing hypothalamic obesity in a patient.

2. The use as claimed in claim 1, wherein hypothalamic obesity is the result of a hypothalamic lesion due to infiltrating disease, tumor, neurosurgery, radiation or head trauma.

3. The use as claimed in claim 1, wherein the hypothalamic obesity is the result of a craniopharyngioma or after the surgical or radiological treatment of the craniopharyngioma.

4. The use as claimed in claim 2, wherein the tumor is an epithelioma, angiosarcoma, cholesteatoma, pinealoma, greminoma, endothelioma, hamartoma, chordoma, colloid cysts, epidermoid, ganglioneuroma, ependymoma, glioma, meningioma, pituitary macroadenoma, teratoma , leukemia, Langerhans cell or metastasis.

5. The use as claimed in claim 2, wherein the disease is sarcoidosis, tuberculosis, araenoiditis, histiocytosis X or encephalitis.

6. The use as claimed in claim 1, wherein the Hypothalamic obesity is the result of a cranial radiotherapy or cerebral aneurysm.

7. The use as claimed in claim 1, where hypothalamic obesity is due to Prader-Willi syndrome or Bardet-Biedi syndrome.

8. The use as claimed in claim 1, wherein hypothalamic obesity is due to a unique genetic mutation.

9. The use of a MetAP-2 inhibitor to prepare a medicament for treating hypothalamic obesity in a patient under treatment of schizophrenia or depression.

10. The use as claimed in claim 9, wherein the patient in treatment of schizophrenia or depression was administered or administered amitriptyline, doxepin, imipramine, clomipramine, maprotin, nortriptyline, trimipramine, paroxetine, mirtazapine, deopramine, isocarboxazid, lithium, valproate, carbamazapine, clozapine, olanzepine, zotepine, quetiapine, chlorpromazine, thioridazine, perphenazine, trifluoperazine, risperidone, clopentioxol or sulpiride.

11. The use of a MetAP-2 inhibitor to prepare a medicament for substantially maintaining body weight or reducing the amount of weight gain in a patient recovering from, or in which, craniopharyngioma surgery or radiological treatment of the patient is initiated. Craniopharyngioma.

12. The use of a MetAP-2 inhibitor to prepare a medication to substantially maintain body weight, or minimize weight gain in a patient suffering from Prader-Willi syndrome or Bardet-Biedi syndrome.

13. The use as claimed in any of claims 1 to 12, wherein the patient is human.

14. The use as claimed in claim 13, where the patient is a child under 18 years of age.

15. The use as claimed in claim 14, where the child is above the 95th percentile for children of the same age and sex or a lower body mass index but which is a clear cause for hypothalamic obesity.

16. The use as claimed in any of claims 1 to 14, wherein said MetAP-2 inhibitor is a substantially irreversible inhibitor.

17. The use as claimed in any of claims 1 to 16, wherein said MetAP-2 inhibitor is selected from the group consisting of a fumagillin, fimagilol or fumagylyl ketone, siRNA, shRNA, an antibody or an antisense compound.

18. The use as claimed in any one of claims 1 to 17, wherein said MetAP-2 inhibitor is selected from O- (4-dimethylaminoethoxycinnamoyl) fumagillol and pharmaceutically acceptable salts thereof.

19. The use as claimed in any of the claims 1 to 15, wherein the MetAP-2 inhibitor is a reversible inhibitor.

20. The use as claimed in claim 13 or 14, wherein the patient has an initial body mass index of at least about 35 kg / m2.

21. The use as claimed in claim 13 or 14, wherein the patient has a body mass index of at least about 40 kg / m2.

22. The use as claimed in any one of claims 1 to 21, wherein the administration of the medicament comprises a subcutaneous or intravenous administration.

23. The use as claimed in any of claims 1 to 21, wherein the administration of the medicament comprises an oral administration.

24. The use of 0- (4-dimethylaminoethoxycinnamoyl) fumagillol or a pharmaceutically acceptable salt thereof to prepare a medicament for treating hypothalamic obesity in a patient, wherein the medicament is adapted to be parentally administrable 2 or 3 times a week.

25. The use as claimed in claim 24, wherein the parental administration comprises subcutaneous administration.

26. The use as claimed in claim 18 or 24, wherein the medicament is adapted to be administrable from about 0.005 to about 0.049 mg / kg of 0- (4-dimethylaminoethoxycinnamoyl) fumagillol or a pharmaceutically acceptable salt thereof.

27. The use as claimed in claim 18 or 24, wherein the medicament is adapted to be administrable from about 0.005 to about 0.9 mg / kg of 0- (4-dimethylaminoethoxycinnamoyl) fumagillol or a pharmaceutically acceptable salt thereof. East.

28. A MetAP-2 inhibitor for use in the treatment and / or minimization of hypothalamic obesity in a patient.

29. The MetAP-2 inhibitor for use according to claim 28, wherein the hypothalamic obesity is the result of a hypothalamic lesion due to an infiltrating disease, tumor, neurosurgery, radiation or head trauma.

30. The MetAP-2 inhibitor to be used according to claim 28, wherein the hypothalamic obesity is the result of a craniopharyngioma or after the surgical or radiological treatment of the craniopharyngioma.

31. The MetAP-2 inhibitor for use according to claim 29, wherein the tumor is an epithelioma, angiosarcoma, cholesteatoma, pinealoma, greminoma, endothelioma, hamartoma, chordoma, colloid cysts, epidermoid, ganglioneuroma, ependymoma, glioma, meningioma, macroadenoma pituitary, teratoma, leukemia, cell Langerhans or metastasis.

32. The MetAP-2 inhibitor for use according to claim 29, wherein the disease is sarcoidosis, tuberculosis, araenoiditis, X histiocytosis or encephalitis.

33. The MetAP-2 inhibitor for use according to claim 28, wherein the hypothalamic obesity is the result of a cranial radiotherapy or cerebral aneurysm.

34. The MetAP-2 inhibitor for use according to claim 28, wherein the hypothalamic obesity is due to the Prader-Willi syndrome or the Bardet-Biedi syndrome.

35. The MetAP-2 inhibitor for use according to claim 28, wherein the hypothalamic obesity is due to a unique genetic mutation.

36. A MetAP-2 inhibitor for use in the treatment of hypothalamic obesity in a patient under treatment of schizophrenia or depression.

37. The MetAP-2 inhibitor for use according to claim 36, wherein the patient under treatment for schizophrenia or depression is administered or administered amitriptyline, doxepin, imipramine, clomipramine, maprotin, nortriptyline, trimipramine, paroxetine, mirtazapine, deopramine , isocarboxazid, lithium, valproate, carbamazapine, clozapine, olanzepine, zotepine, quetiapine, chlorpromazine, thioridazine, perphenazine, trifluoperazine, risperidone, clopentioxol or sulpiride.

38. A MetAP-2 inhibitor for use in the substantial maintenance of body weight or reduction of the amount of weight gain in a patient recovering from, or in which, the surgery of the patient is initiated. Craniopharyngioma or radiological treatment of craniopharyngioma.

39. A MetAP-2 inhibitor for use in the substantial maintenance of body weight, or minimization of weight gain in a patient suffering from Prader-Willi syndrome or Bardet-Biedi syndrome.

40. The MetAP-2 inhibitor for use according to any of claims 28 to 39, wherein the patient is human.

41. The MetAP-2 inhibitor to be used according to claim 40, wherein the patient is a child under 18 years of age.

42. The MetAP-2 inhibitor for use according to claim 41, wherein the child is above the 95th percentile for children of the same age and sex or a lower body mass index but which is a clear cause for hypothalamic obesity .

43. The MetAP-2 inhibitor for use according to any of claims 28 to 41, wherein said MetAP-2 inhibitor is a substantially irreversible inhibitor.

44. The MetAP-2 inhibitor for use according to any of claims 28 to 43, wherein said MetAP-2 inhibitor is selected from the group consisting of a fumagillin, fimagilol or fumagilyl ketone, siRNA, shRNA, an antibody or a compound antisense

45. The MetAP-2 inhibitor for use according to any of claims 28 to 44, wherein said MetAP-2 inhibitor is selected from 0- (4-dimethylaminoethoxycinnamoyl) fumagillol and salts pharmaceutically acceptable of this.

46. The MetAP-2 inhibitor for use according to any of claims 28 to 42, wherein the MetAP-2 inhibitor is a reversible inhibitor.

47. The MetAP-2 inhibitor for use according to claim 40 or 41, wherein the patient has an initial body mass index of at least about 35 kg / m2.

48. The MetAP-2 inhibitor for use according to claim 40 or 41, wherein the patient has a body mass index of at least about 40 kg / m2.

49. The MetAP-2 inhibitor for use according to any of claims 28 to 48, wherein the administration of the MetAP-2 inhibitor comprises a subcutaneous or intravenous administration.

50. The MetAP-2 inhibitor for use according to any of claims 28 to 48, wherein the administration of the MetAP-2 inhibitor comprises an oral administration.

51. 0- (4-dimethylaminoethoxycinmoyl) fumagillol or a pharmaceutically acceptable salt thereof for use in the treatment of hypothalamic obesity in a patient, wherein the 0- (4-dimethylaminoethoxycinnamoyl) fumagillol or a pharmaceutically acceptable salt thereof is adapted to be administrable parentally 2 or 3 times a week.

52. The 0- (4-dimethylaminoethoxycinmoyl) fumagillol or a pharmaceutically acceptable salt thereof for use according to claim 51, wherein the parental administration comprises subcutaneous administration.

53. The 0- (4-dimethylaminoethoxycinmoyl) fumagillol or a pharmaceutically acceptable salt thereof for use according to claim 45 or 51, wherein the 0- (4-dimethylaminoethoxycinnamoyl) fumagillol or a pharmaceutically acceptable salt thereof is adapted to be administrable from about 0.005 to about 0.049 mg / kg of 0- (4-dimethylaminoethoxycinnamoyl) fumagillol or a pharmaceutically acceptable salt thereof.

54. The 0- (4-dimethylaminoethoxyaminoyl) fumagillol or a pharmaceutically acceptable salt thereof for use according to claim 45 or 51, wherein the 0- (4-dimethylaminoethoxycinnamoyl) fumagillol or a pharmaceutically acceptable salt thereof is adapted to be administrable from about 0.005 to about 0.9 mg / kg of 0- (4-dimethylaminoethoxycinnamoyl) fumagillol or a pharmaceutically acceptable salt thereof.